Coronavirus SARS-CoV2: BESSY II data accelerate drug development
Schematic representation of the coronavirus protease. The enzyme comes as a dimer consisting of two identical molecules. A part of the dimer is shown in colour (green and purple), the other in grey. The small molecule in yellow binds to the active centre of the protease and could be used as blueprint for an inhibitor. © H. Tabermann/HZB
Filmclip: At BESSY II, the main protease of SARS-CoV2 has been decoded. This might help to develop drugs. © HG Medien/HZB
01:11A coronavirus is keeping the world in suspense. SARS-CoV-2 is highly infectious and can cause severe pneumonia with respiratory distress (COVID-19). Scientists are doing research in order to prevent the viruses from multiplying. A team from the University of Lübeck and from Helmholtz Centre for Infection Research (HZI) has now found a promising approach. Using the high-intensity X-ray light from the Berlin synchrotron source BESSY II, they have decoded the three-dimensional architecture of the main protease of SARS-CoV-2. This protein is involved in the reproduction of the virus. Analysing its 3D architecture allows the systematic development of drugs which inhibit the reproduction of the virus.
Teams around the world are working hard to develop active substances against SARS-CoV-2. The structural analysis of functional proteins of the virus is very helpful for this goal. The function of a protein is closely related to its 3D architecture. If this 3D architecture is known, it is possible to identify specific points of attack for active substances.
Inhibiting the reproduction
A special protein is involved in the reproduction of the virus: the viral main protease (Mpro or also 3CLpro). A team led by Prof. Dr. Rolf Hilgenfeld, University of Lübeck, has now decoded the 3D architecture of the main protease of SARS-CoV-2. The researchers have used the high-intensity X-ray light from the BESSY II facility of the Helmholtz-Zentrum Berlin.
Fast track at BESSY II
"For such issues of highest relevance, we can offer fast track access to our instruments", says Dr. Manfred Weiss, who heads the Research Group Macromolecular Crystallography (MX) at HZB. At the so-called MX instruments tiny protein crystals can be analysed with highly brilliant X-ray light. The images contain information about the 3D architecture of the protein molecules. The complex shape of the protein molecule and its electron density is then calculated by computer algorithms.
Targets for active substances
The 3D architecture provides concrete starting points for developing active substances or inhibitors. These drugs could dock specifically to target points of the macromolecule and impede its function. Rolf Hilgenfeld is a world-renowned expert in the field of virology and already developed an inhibitor against the SARS-virus during the 2002/2003 SARS pandemic. In 2016, he succeeded in deciphering an enzyme of the Zika virus.
Science, 20. March 2020: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld
DOI: 10.1126/science.abb3405
- Protein crystallography at BESSY II: faster, better and more and more automaticMany diseases are linked to malfunctions of proteins in the organism. The three-dimensional architecture of these molecules is often highly complex, but it can provide valuable insights into biological processes and the development of drugs. X-ray diffraction at the MX beamlines of BESSY II can be used to decipher the 3D structure of proteins. To date, more than 5000 structures have been solved at the three MX beamlines. Here, we present a review and an outlook with Manfred Weiss, head of the research group for macromolecular crystallography.
- 5000th protein structure at BESSY II: Starting point for a COVID drugMany proteins have a complex architecture that enables biological functions. Molecules can bind to specific sites on a protein and alter its function. A team at HZB has now investigated the Nsp1 protein, which plays a role in infection with the SARS-CoV-2 virus. They analysed protein crystals, previously mixed with molecules from a fragment library, and discovered a total of 21 candidates as starting points for drug development. At the same time, they also decoded the 5000th structure at BESSY II.
- What Zinc concentration in teeth revealsTeeth are composites of mineral and protein, with a bulk of bony dentin that is highly porous. This structure is allows teeth to be both strong and sensitive. Besides calcium and phosphate, teeth contain trace elements such as zinc. Using complementary microscopy imaging techniques, a team from Charité Berlin, TU Berlin and HZB has quantified the distribution of natural zinc along and across teeth in 3 dimensions. The team found that, as porosity in dentine increases towards the pulp, zinc concentration increases 5~10 fold. These results help to understand the influence of widely-used zinc-containing biomaterials (e.g. filling) and could inspire improvements in dental medicine.